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Supervoltage radiotherapy for Graves' ophthalmopathy: CCABC technique and results
int. J. Radmtion Oncology &ol Phys., Vol. I I. pp. 2085-2090 Printed ia the U.S.A. All rights reserved.
Copyright
0360-3016/X5 803.00 + .OO Q 1985 Pergamon Press Ltd.
??Original Contribution
RADIOTHERAPY FOR GRAVES’ OPHTHAL CCABC TECHNIQUE AND RESULTS
UPERVOLTAGE
LIVOTTO,
M.D.,”
e.
M. LUDGATE,
M.D.,’ L. H. ALLEN,
M.D.2
AND J.
THY:
OBTMAN,
l14.D.~
‘Cancer Control Agency of British Columbia; *Division of Ophthalmology, Vancouver General Hospital, University of British Columbia A treatment technique employing retrobulbar supervoltage radiotherapy (XRT) in Graves’ ophtbalmopathy is described. Twenty-eight patients have been treated and followed between 1980-1983. Twenty-six of 28 patients (93%) showed some response, with 19/28 (68%) having a good to excellent response. Four of 28 (14%) had recurrent symptoms post-XRT. Soft tissue signs and symptoms were relieved and disease progression arrested in the majority of patients, but proptosis and ophthalmoplegia responded poorly. High dose corticosteroids have generally been the alternative form of therapy for this disease. Post-XRT, 24/28 (86%) of patients have had no further steroid requirements, and been spared the associated complications. Treatment was well tolerated, with only five patients (18%) demonstrating a transient worsening of symptoms which settled entirely within 2 weeks. No long-term complications have been encountered. Eleven patients had post-XRT CT scans which were compared to pre-treatment scans and clinical response. Nine of 11 patients (82%) had CT changes in general agreement with the observed clinical response, but the degree of involvement seen on the initial CT scan was not predictive of response nor the risk of relapse. XRT with the described technique is felt to be an effective, safe, and practical approach to the disabling and disfiguring complications of severe Graves’ ophthalmopathy. Graves’ Qpbthalmopathy,
Radiotherapy, CT scans.
NTRODUCTION
Initial reports of XRT in this disease were discouraging, but Donaldson et ~1.~ reported improved results with a well collimated, supervoltage technique, which has subsequently been used by others.““6 This paper describes our experience with a technique differing in several important aspects.
Graves’ ophthalmopathy is one component of a multisystem disorder including hyperthyroid&m and an infiltrative dermopathy. The etiology of Graves’ disease remains unknown, although evidence supports an aberrant immune response, possibly cell mediated.‘O An intraorbital, retrobulbar inflammatory infiltrate increases soft tissue bulk secondarily impairing drainage of the conjunctiva and orbit, producing lid swelling, chemosis and injection. With disease progression, potentially irreversible proptosis and ophthalmoplegia develop. Apical pressure causing optic neuropathy may acutely threaten vision. The changes in Graves’ ophthalmopathy as adopted by the American Thyroid Association (ATA)14 (Table l), have proven useful in objectively comparing results of treatment.4,6,‘6 Mild ophthalmopathy may be treated symptomatically. More severe disease has been treated with corticosteroids’,2*16 or other anti-inflammatory agen@,12>13 and by orbital radiotherapy (XRT).1,4,6,“‘16
Thirty-two patients were referred to the CCABC* for XRT between January 1980 and December 1983, after initial assessment by a consulting ophthalmologist (JR). Patients were referred for radiotherapy if they had major soft tissue symptoms unalleviated by conservative measures and requiring medical intervention. All would have fit in a category treatable by corticosteroids and either elected not to have steroids, had relative contraindications to steroid use based on age or systemic disease, could not be monitored on corticosteroids as they resided in small
Presented in part by Dr. I. A. Olivotto at the Canadian Association of Radiologists’ 47th Annual Meeting in Vancouver, B.C., June 1984. Reprint requests to: Dr. I. A. Olivotto, Cancer Control Agency of British Columbia, A. Maxwell Evans Clinic, 600 West 10th Ave., Vancouver, B.C., V5Z 4E6. Acknowledgments-The authors wish to thank Dr. Robert Nu-
gent for assistance in grading the CT scans, Mrs. Patricia Findlay and Mrs. Brenda McParland in preparation of the manuscript, and the Medical Illustration Department at CCABC for preparation of the illustrations. Accepted for publication 29 July 1985. * 4. Maxwell Evans Clinic; Cancer Control Agency of B.C., 600 West 10th Avenue, Vancouver, B.C. V5Z 4E6. 2085
METHODS
AND
MATERIALS
2086
Radiation Oncology @ Biology Table I. American thyroid association ophthalmopathy classification Class
Involvement
0
No symptoms or signs Only lid lag or retraction; no symptoms Soft-tissue changes Proptosis Extraocular muscle motility impairment Cornea1 ulcer Optic nerve involvement
1 2 3 4 5 6 Reproduced 982.14
(by permission)
from Werner,
S. C., Table 1, p.
communities, had developed significant steroid side effects or had failed after discontinuation of steroids. Two of the patients were severe thyroid ophthalmopathies with optic neuropathy that had not responded to corticosteroids. The CCABC and private office records, pre and posttreatment clinical photographs, and orbital CT scans where available have been reviewed. Patients were followed at 2 weeks, 1 month and 2 to 3 monthly visits posttreatment. Follow-up ranged from 2-33 months with a median and mean of 17 months. Clinical criterion used for assessing responses were recorded at each visit. They consisted of a one to four point system for preseptal edema, conjunctival injection and chemosis, visual acuity assessment, measurement of the interpalpebral fissure, orbital tension based on ballottement, exophthalmometry measurement as well as vertical and horizontal measurements of ocular displacement, quantitation of extraocular movements in all fields of gaze by degree of limitation, Maddox rod testing for manifest and nonmanifest deviation, intraocular pressure measurement in the primary position and upgaze, biomicroscopic examination of the cornea and routine fundus examination with the indirect ophthalmoscope. From this data mean values were assigned to each ophthalmopathy class based on the ATA classification (Table 1). Pre- and posttreatment ophthalmopathy indices were calculated as proposed by Donaldson et aL6 Pre-XRT indices ranged from 3.5-10 with a mean of 5.9. Patient characteristics Four patients were non-evaluable. One refused XRT, one was lost to follow-up, and one died suddenly of unrelated disease prior to any recorded follow-up. One patient spontaneously improved and did not receive XRT. These patients were excluded from analysis. There were 23 females and 5 males in the evaluable group. Age ranged from 36 to 72 with a mean of 58 years, Nine patients (all female) had a positive family history for thyroid disease. All but one (due to excessive replacement thyroxin) were euthyroid at the time of XRT. Twenty-four had previously been treated for hyperthyroidism, two for hypothyroidism and two patients had
December 1985, Volume ! 1, Number 12
euthyroid Graves’ ophthalmopathy. The duration of preXRT eye signs and symptoms ranged from 2 months to 5 years with a mean of 9 months and a median of 10.5 months. Four patients had visual impairment, but no patient had acute optic neuropathy. Fifteen of 28 patients (54%) had previously been treated with or were receiving steroids at the time of referral. Generally large doses (30-60 mg of Prednisone daily) had been given for many weeks to months. Steroids were tapered off (5 mg per week) once XRT began. Iodineof 15 (60%) had developed significant side effects (agitation, depression, peptic ulcer disease, marked Cushingoid features). Thirteen of 15 patients had failed or had recurrence of symptoms when steroids were tapered off. Seven dditional patients were referred because of absolute or relative contraindications to the use of steroids. Radiotherapy technique A cellulose acetate head and neck treatment shell for immobilization and localization was constructed for all patients. A contour of the shell at the orbital level was used to calculate output factors to achieve a prescribed midline dose of 2000 cGy in 10 fractions over 12 days (Fig. 1). Treatment is delivered on a 4 MeV linear accelerator. The retro-orbital tissues received between 10 1 and 104% of the prescribed dose (Fig. 1). Step I (Figure 2a). The patient is placed supine in the treatment shell. The lateral and midline locating lasers are aligned. The gantry is placed horizontal (0 or I80 degrees). Diaphragm settings establish a 4.0 X 4.0 cm light field. By adjusting the couch height the light field is brought to skim just anterior to the ipsilateral cornea. Step 2. To establish the beam axis (line CD, Fig. 1) parallel to a line tangent to both cornea (line AR, Fig. l), the gantry is rotated exactly 180 degrees and minor adjustments to accommodate unequal amounts of proptosis are made in the couch height and gantry rotation to bring the light field on the second side just anterior to the second cornea. Changes of 2-3 degrees have usually been suffi-
FIG. 1~ Contour in treatment shell. AB is a line tangent to the anterior limits of both cornea. CD, the beam axis, is parallel to and 2.0 cm posterior to line AB. Isodose contours as marked.
XRT for Graves’ ophthalmopathy
I. A.
2081
OworTo et al.
FIG. 2. Sequential change in diaphragm settings to establish final treatment portal (c). Shading represents full thickness lead block. See text for details of technique. (a) Step 1, 4.0 X 4.0 cm; (b) Step 3, 8.0 X 4.0 cm; (c) Step 4, 8.0 :< 4.0 with anterior 4 cm blocked with lead.
The gantry is then rotated back 180 degrees to recheck the first side returning the 4.0 X 4.0 light field just anterior to the first cornea. The exact gantry angles are recorded for uniformity of the day to day setup. Step 3 (Fig. 2b). The antero-posterior diaphragm setting is widened to 8.0 cm. Step 4 (Fig. 2~). The anterior 4.0 cm is blocked with 3 inches (7.8 cm) of lead blocking reducing direct transmission to less than 2%. This technique achieves a 4.0 X 4.0 cm treatment portal, the anterior limit of which is aligned along the central axis of the machine and is 2 cm posterior to a line tangent to both cornea. The lead block eliminates divergence anteriorly. The treatment volume encompasses the posterior 0.5 cm of the globe and the entire retrobulbar tissue. Simulator check films are obtained to ensure that the pituitary fossa is excluded posteriorly. All patients are treated bilaterally, because in our experience CT and ultrasound scans demonstrate bilateral involvement, even with minimal signs and symptoms in one eye. We feel the treatment volume as designed encompasses most of the muscular portion of the extraocular muscles since the anterior portion is mainly tendon. Review of CT scans in these patients indicates that it is the posterior 3-s of the muscle that is involved in the inflammatory process. That part of the muscle is included with this technique. Computer simulation estimates a lens dose of less than 5% (100 cGy in 10 fractions in 12 days). Thermoluminescent dosimetric (TLD) readings just anterior to the lateral and medial canthi were performed to confirm this. A mean of three measurements predict a total dose of 98 +- 4.5 cCy. This is less than the estimated cataractogenic dose given as a single exposure.’ This technique varies from Donaldson et ~1.~in (a) the use of a treatment shell for stabilization and localization; (b) the anterior cornea is used as a landmark rather than the lateral bony canthus so that varying degrees of propcient.
tosis can be accommodated, (c) t e anterior beam edge is more sharply defined by the lead blocking rather than by diaphragm settings, and (d) the absence of superior or inferior field blocking. These points should add precision, flexibility and safety especially in minimizing the total lens dose. CT scans Patients underwent orbital CT scans, ultrasonography or both prior to XRT. Bilateral involvement was seen in all patients. Eleven patients were randomly selected to have post-XRT CT scans. These were compared to preXRT scans and correlated with clinical response. Tangential (axial) and coronal scans made it possible to assess muscle changes in the superior, inferior, lateral and medial recti as well as the superior oblique (Fig. 3). The inferior oblique is not well visualized on orbital CT scans. Involvement was scored as 0 = normal, 1 = mild, 2 = moderate and 3 = severe. A CT-muscle index was derived as the sum of the scores of each muscle for each eye separately. The change in the CT muscle index was compared to the change in the ophthalmopathy index in individual patients. Crowding of the optic nerve at the apex of the orbit was scored as 0 = normal fat plane, 1 = diminished fat plane, 2 = encroachment with loss of the fat plane around ~50% ofthe circumference of the optic nerve and 3 = >50% of the circumference of the optic nerve having lost its fat plane. Orbital fat density was difficult to score as density settings and technique varied between scans and was therefore scored simply as normal or increased. RESULTS Clinical’response to radiotherapy Treatment was well tolerated. Five patients had a transient worsening of edema or foreign body sensation, but this cleared by the end of XRT. In this short follow-up (median 17 months) there have been no late XRT effects.
December
1985, Volume 11) Number i2
FIG. 3. Left: Pre-XRT; Right: 6 months post-XRT. Left: Axial (a) and coronal (c) scans of patients with a moderate degree of thyroid ophthalmopathy characterized by tearing, lid swelling, widened interpalpebral fissure, chemosis and punctuate staring of the cornea, with limitation of movement and a small esotropian. Total presenting ophthalmopathy index was 4.5. Right: Axial (b) and coronal (d) scans in the same plane as the pretreatment scans. Note diminution in the size of the muscle bellies on both axial and coronal scans. Overall index at the time of second scan was 1.5.
Table 2 outlines the overall response based on the clinical criteria of Donaldson et al.‘j Twenty-six of 28 patients (93%) showed some response. Nineteen of 28 (68%) demonstrated a good to excellent response. There is a trend toward greater improvement in the mean ophthalmopathy indices (Table 3), in association with a better clinical response confirming the index as a useful measure of response. No patients returned entirely to normal. Four patients had initial fair to excellent responses, but then had disease recurrence 3 to 7 months (mean 4.8 months) later. Three have gone on to have orbital decompression, and the fourth is being maintained on corticosteroids. A better response was not seen in patients
with eye signs and symptoms present for less than 12 months compared to those with a longer duration. The soft tissue signs and symptoms responded much more favorably than proptosis or ophthalmoplegia (Table 4). Cornea1 staining resolved in parallel with the reduction in edema and chemosis. The few patients with visual impairment (generally mild) had favorable responses (Table 4). There was no difference in response in the two patients with euthyroid ophthalmopathy compared to those patients who were originally hyper or hypothyroid. There was also no measurable difference in response of either the mean ophthalmopathy index or the likelihood that
XRT for Graves’ ophthalmopathy Table 2. Clinical response Number
Response* Excellent Good Fair Transient No response Worse
Table 3. Change in mean ophthalmopathy
to XRT Percentage
lo/28 9128 3128 4128 2128 O/28
* Response criteria as defined by Donaldson “‘transient”, which refers to disease progression quiring further intervention.
2089
I. 1~.GLlvoTTo et al.
36 32 11 14 I 0
et al6 except after XRT re-
Response Excellent (lo)* Good (9) Fair (3) Transient (4) No response (2)
index
Pre
Post
Net change
6.5 4.9 5.2 7.1 4.0
3.4 2.5 3.0 4.9 4.5
-3.1 -2.4 -2.2 -2.2 f0.5
* Number of patients in category. Net change in ophthalmopathy index is correlated to response as assessed by clinical criteria.
Teng et al.” reported good recriteria. 1,4,6,1’ sponses in only 35% of their patients, but their population had less severe disease and many had eye symptoms for long durations. The best response in this and other series is on soft tissue signs and symptoms. Transient worsening of symptoms may occur at the start of XRT (5/28: 18% of this series), but this usually resolves by the end of the second week,6 Soft tissue changes respond rapidly (2 to 4 weeks).6,” A better response in those patients with disease symptoms for less than 12 months was not demonstrated in this series in contrast to that reported elsewhere.‘,6,‘6 Nineteen of 28 patients had some degree of measurable proptosis at presentation. The mean reduction was less than 1 mm, confirming the experience of others.‘,6,16 Proptosis responds slowly if at all (3 to 7 months), and patients continue to have more exophthalmos than in normal or hyperthyroid patients without proptosis.i6 Once severe ophthalmoplegia is present only minimal improvement can be expected. None of these patients had acute compressive optic neuropathy. Others have found this to respond rapidly and effectively restoring normal visual acuity in the four such patients reported.‘,6
response
would be completely rea transient flare of symptoms while receiving XRT compared to patients not experiencing such a flare. A total of 14 patients have undergone some surgery post-XRT with four having more than one operation. Three patients required orbital decompression to control symptoms. The rest of the patients had stable disease. Seven muscle recession procedures resulted in 6/7 patients currently with no diplopia w-hile reading or with distance vision. Additionally, seven patients had bilateral blepharoplasties or mullerectomies mainly to improve cosmesis. soft tissue
lieved
signs
and
symptoms
in the five patients
having
Effect on steroid requirements Overall 20/28 patients (7 1%) were referred for failure (8 patients), adverse side effects (5 patients), or relative contraindications to (7 patients) the use of high dose steroids. Seventeen of 20 patients (85%) of this group have no further steroid requirements, In the total group, 4/28 ( 14%) have continued steroid requirements, but the majority, 24/28 (86%) were spared the long-term complications of high dose corticosteroids. Correlation of CT scans with radiotherapy response T, definite changes are seen in all parameters considered (Fig. 3). Nine of 11 patients (82%) had a good correlation between the change in ophthalmopathy index and change in the CT-muscle index. Those patients with an excellent clinical response and greater changes in the ophthalmopathy index had greater changes in the mean CT-muscle score. Patients with no or fair response had smaller CT-muscle index changes and less resolution of apical crowding. The initial degree of involvement as assessed by CT scan was not predictive of the clinical response nor the likelihood of relapse. ISCUSSION
Response Sixty-eight percent of the study population had a good to excellent response, although no patient had eye changes return entirely to normal. This is in agreement with the literature where good to excellent responses have been reported in 35-72% of patients using similar grading and
Radiation technique This technique treats the inflamed retro-orbital tissue, and as it does not rely on bony landmarks, may be used where proptosis is unequal or changes during the course of treatment. Acute XRT side effects are mild and transient. There have been no long-term complications to date in this or other series. 1,6,11The risk of cataractogenesis Table 4. Response
Class 2 3 4 5 6
Present pre-XRT* 28 19 28 13 4
Resolution? 61 21 4 70 50
to XRT vs class
Improved? 32 5 39 15 50
No change? 7 74 57 15 -
* I\Jumber of initial 28 patients with involvement t Percentage of involved pre-XRT Percentage of patients with initial involvement of a given ophthalmopathy sign showing improvement post-XRT. Resolution. = complete disappearance or return to normal. Improved = some improvement but less than resolution
2090
Radiation Oncology @ Biology Ib Physics
and hypopituitarism are negligible with the dose delivered to those structures by this technique. Although there are reports of second malignancy arising after XRT for benign diseases,3,9 the risk in this setting is felt to be small. The alternative to XRT has generally been the use of corticosteroids. No randomized trials comparing XRT alone vs steroids alone have been reported. Bartalena et al. ’recently reported a trial comparing orbital cobalt XRT with steroids vs steroids alone (70-80 mg Methylprednisolone X 3 weeks then slowly tapering over 5-6 months). Combined treatment gave significantly better results than steroids alone. However, “most cases” developed Cushingoid features.] In our experience, similar steroid doses have been required in order to control disease manifestations, resulting in significant and limiting side effects. Five patients (18%) were initially referred because of limiting adverse effects and seven (25%) because of relative contraindications to the use of high dose steroids. Additionally, in this population and others6,“j failure on or relapse after steroid use was not predictive of a lack of response to XRT. Twenty-four of 28 patients (86%) in this series have had no further steroid requirements postXRT. We feel this reduction in steroid use is a significant benefit. There may be a subgroup of patients who will respond to either XRT or steroids. To minimize toxicity we recommend the early use of XRT in those patients not easily controlled by a short course of modest dose steroids, and in elderly patients. Orbital CT scans7 and ultrasonography” have been useful diagnostically. Extraocular muscle and orbital fat
December 1985, Volume 1 i, Number 12
changes parallel clinical response post-XRT (Fig. 3). The severity of initial involvement as assessed by CT scan, however, is not predictive of either the degree of response nor the likelihood of relapse. Several questions remain about the use of XRT in Graves’ ophthalmopathy, not the least of which is, why does it work? Local immunosuppression is attractive theoretically and was the initial impetus for the trial of this modality. If an aberrant, systemic immune response is the basis of the disease process, it is surprising that symptomatic recurrence is not more common. Possibly the XRT interferes with a target other than inflammatory cells, such as the fibroblast or muscle membrane components, to prevent the development of infiltrative changes.6 In summary, with the described technique, a good to excellent response can be expected in approximately 70% of patients with negligible acute or long-term complications. XRT is indicated for: 1. Rapidly progressive severe ophthalmopathy. 2. Troublesome soft tissue signs and symptoms. 3. Patients in whom steroids are contraindicated. 4. Patients not controlled by or developing side effects on modest doses of steroids.
The effect of XRT as a primary modality in very early disease is not known. Potentially XRT may permanently arrest disease progression and prevent the disabling and disfiguring problems associated with proptosis and ophthalmoplegia. The role of XRT in this early group is currently being assessed at our institution.
REFERENCES 1. Bartalena, L., Marcocci, C., Chiovata, L., Laddaga, M., Lepri, G., Andreani, D., Cavallacci, G., Baschieri, L., Pinchera, A.: Orbital cobalt irradiation combined with systemic corticosteroids for Graves’ ophthalmopathy: Comparison with systemic corticosteroids alone. J. Clin. Endocrinol. Metab. 56(6): 1139-l 144, 1983. 2. Burrow, G.N., Mitchell, MS., Howard, R.O.: Immunosuppressive therapy for the eye changes of Graves’ disease. J. C/in. Endocrinol. 31: 307-311, 1970. 3. Court Brown, W.M., Doll, R.: Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. Br. Med. J. 2: 1327-1332, 1965. E.E., Lobes, L., Sudarsanam, A.: Radiation 4. Covington, therapy for exophthalmos: Report of seven cases. Radiology 122: 797-799, 1977. 5. Dandona, P., Marshall, N.J., Bidey, S.P., Nathan, A., Havard, C.W.H.: Successful treatment of exophthalmas and Br. Med. J. 1: pretibial myxoedema with plasmapheresis. 374-376, 1979. 6. Donaldson, S.S., Bagshaw, M.A., Kriss, V.P.: Supervoltage J. Clin. orbital radiotherapy for Graves’ ophthalmopathy. Endocrinol. Metab. 37(2): 276-285, 1973. 7. Feldon, SE., Weiner, J.M.: Clinical significance of extraocular muscle volumes in Graves’ ophthalmopathy: A quantitative computed tomography study. Arch. Ophthalmol. lOO(8): 1266-1269, 1982. 8. Merriam, Jr. G.R., Focht, E.F.: A clinical study of radiation cataracts and the relationship to dose. Am. J. Roentgenol. 77: 759-785, 1957.
9. Saenger, EL., Silverman, F.N., Sperling, T.D., Turner, M.E.: Neoplasia following therapeutic irradiation for benign conditions in childhood. Radiology 74(6): 889-904, 1960. A clin10. Sergott, R.C., Glaser, J.S.: Graves’ ophthalmopathy. ical and immunologic review. Surv. Ophthalmol. 26( 1): l21, 1981. 11. Teng, C.S., Crombie, A.L., Hall, R., Ross, W.M.: An evaluation of supervoltage orbital irradiation for Graves’ ophthalmopathy. Chin. Endocrinol. (Oxf.) 13(6): 545-55 1, 1980. 12. Wall, J.R., Strakosch, C.R., Fang, S.L., Ingbar, S.H., Braverman, L.E.: Thyroid binding antibodies and other immunological abnormalities in patients with Graves’ ophthalmopathy: Effect of treatment with Cyclophosphamide. Clin. Endocrinol. (Osf.) lO( 1): 79-9 1, 1979. 13. Weetman, A.P., Ludgate, M., Mills, P.V., McGregor, A.M., Beck, L., Lazarus, J.H., Hall, R.: Cyclosporin improves Graves’ ophthalmopathy. Lancet 2: 486-489, 1983. 14. Werner, SC.: Classification of the eye changes of Graves’ disease. J. Clin. Endocrinol. 29: 982-984, 1969. 15. Yamamoto, K., Itoh, K., Yoshida, S., Saito, K.; Sakamoto, Y., Matsuda, A., Saito, T., Kuzuya, T.: A quantitative analysis of orbital soft tissues in Graves’ disease based on Bmode ultrasonography. Endocrinol. Jpn. 26(2): 255-26 1, 1979. 16. Yamamoto, K., Saito, K., Takai, T., Yoshida, S.: Treatment of Graves’ ophthalmopathy by steroid therapy, orbital radiation therapy, plasmapheresis and thyroxine replacement. Endocrinol. Jpn. 29(4): 495-50 1, 1982.
Copyright
0360-3016/X5 803.00 + .OO Q 1985 Pergamon Press Ltd.
??Original Contribution
RADIOTHERAPY FOR GRAVES’ OPHTHAL CCABC TECHNIQUE AND RESULTS
UPERVOLTAGE
LIVOTTO,
M.D.,”
e.
M. LUDGATE,
M.D.,’ L. H. ALLEN,
M.D.2
AND J.
THY:
OBTMAN,
l14.D.~
‘Cancer Control Agency of British Columbia; *Division of Ophthalmology, Vancouver General Hospital, University of British Columbia A treatment technique employing retrobulbar supervoltage radiotherapy (XRT) in Graves’ ophtbalmopathy is described. Twenty-eight patients have been treated and followed between 1980-1983. Twenty-six of 28 patients (93%) showed some response, with 19/28 (68%) having a good to excellent response. Four of 28 (14%) had recurrent symptoms post-XRT. Soft tissue signs and symptoms were relieved and disease progression arrested in the majority of patients, but proptosis and ophthalmoplegia responded poorly. High dose corticosteroids have generally been the alternative form of therapy for this disease. Post-XRT, 24/28 (86%) of patients have had no further steroid requirements, and been spared the associated complications. Treatment was well tolerated, with only five patients (18%) demonstrating a transient worsening of symptoms which settled entirely within 2 weeks. No long-term complications have been encountered. Eleven patients had post-XRT CT scans which were compared to pre-treatment scans and clinical response. Nine of 11 patients (82%) had CT changes in general agreement with the observed clinical response, but the degree of involvement seen on the initial CT scan was not predictive of response nor the risk of relapse. XRT with the described technique is felt to be an effective, safe, and practical approach to the disabling and disfiguring complications of severe Graves’ ophthalmopathy. Graves’ Qpbthalmopathy,
Radiotherapy, CT scans.
NTRODUCTION
Initial reports of XRT in this disease were discouraging, but Donaldson et ~1.~ reported improved results with a well collimated, supervoltage technique, which has subsequently been used by others.““6 This paper describes our experience with a technique differing in several important aspects.
Graves’ ophthalmopathy is one component of a multisystem disorder including hyperthyroid&m and an infiltrative dermopathy. The etiology of Graves’ disease remains unknown, although evidence supports an aberrant immune response, possibly cell mediated.‘O An intraorbital, retrobulbar inflammatory infiltrate increases soft tissue bulk secondarily impairing drainage of the conjunctiva and orbit, producing lid swelling, chemosis and injection. With disease progression, potentially irreversible proptosis and ophthalmoplegia develop. Apical pressure causing optic neuropathy may acutely threaten vision. The changes in Graves’ ophthalmopathy as adopted by the American Thyroid Association (ATA)14 (Table l), have proven useful in objectively comparing results of treatment.4,6,‘6 Mild ophthalmopathy may be treated symptomatically. More severe disease has been treated with corticosteroids’,2*16 or other anti-inflammatory agen@,12>13 and by orbital radiotherapy (XRT).1,4,6,“‘16
Thirty-two patients were referred to the CCABC* for XRT between January 1980 and December 1983, after initial assessment by a consulting ophthalmologist (JR). Patients were referred for radiotherapy if they had major soft tissue symptoms unalleviated by conservative measures and requiring medical intervention. All would have fit in a category treatable by corticosteroids and either elected not to have steroids, had relative contraindications to steroid use based on age or systemic disease, could not be monitored on corticosteroids as they resided in small
Presented in part by Dr. I. A. Olivotto at the Canadian Association of Radiologists’ 47th Annual Meeting in Vancouver, B.C., June 1984. Reprint requests to: Dr. I. A. Olivotto, Cancer Control Agency of British Columbia, A. Maxwell Evans Clinic, 600 West 10th Ave., Vancouver, B.C., V5Z 4E6. Acknowledgments-The authors wish to thank Dr. Robert Nu-
gent for assistance in grading the CT scans, Mrs. Patricia Findlay and Mrs. Brenda McParland in preparation of the manuscript, and the Medical Illustration Department at CCABC for preparation of the illustrations. Accepted for publication 29 July 1985. * 4. Maxwell Evans Clinic; Cancer Control Agency of B.C., 600 West 10th Avenue, Vancouver, B.C. V5Z 4E6. 2085
METHODS
AND
MATERIALS
2086
Radiation Oncology @ Biology Table I. American thyroid association ophthalmopathy classification Class
Involvement
0
No symptoms or signs Only lid lag or retraction; no symptoms Soft-tissue changes Proptosis Extraocular muscle motility impairment Cornea1 ulcer Optic nerve involvement
1 2 3 4 5 6 Reproduced 982.14
(by permission)
from Werner,
S. C., Table 1, p.
communities, had developed significant steroid side effects or had failed after discontinuation of steroids. Two of the patients were severe thyroid ophthalmopathies with optic neuropathy that had not responded to corticosteroids. The CCABC and private office records, pre and posttreatment clinical photographs, and orbital CT scans where available have been reviewed. Patients were followed at 2 weeks, 1 month and 2 to 3 monthly visits posttreatment. Follow-up ranged from 2-33 months with a median and mean of 17 months. Clinical criterion used for assessing responses were recorded at each visit. They consisted of a one to four point system for preseptal edema, conjunctival injection and chemosis, visual acuity assessment, measurement of the interpalpebral fissure, orbital tension based on ballottement, exophthalmometry measurement as well as vertical and horizontal measurements of ocular displacement, quantitation of extraocular movements in all fields of gaze by degree of limitation, Maddox rod testing for manifest and nonmanifest deviation, intraocular pressure measurement in the primary position and upgaze, biomicroscopic examination of the cornea and routine fundus examination with the indirect ophthalmoscope. From this data mean values were assigned to each ophthalmopathy class based on the ATA classification (Table 1). Pre- and posttreatment ophthalmopathy indices were calculated as proposed by Donaldson et aL6 Pre-XRT indices ranged from 3.5-10 with a mean of 5.9. Patient characteristics Four patients were non-evaluable. One refused XRT, one was lost to follow-up, and one died suddenly of unrelated disease prior to any recorded follow-up. One patient spontaneously improved and did not receive XRT. These patients were excluded from analysis. There were 23 females and 5 males in the evaluable group. Age ranged from 36 to 72 with a mean of 58 years, Nine patients (all female) had a positive family history for thyroid disease. All but one (due to excessive replacement thyroxin) were euthyroid at the time of XRT. Twenty-four had previously been treated for hyperthyroidism, two for hypothyroidism and two patients had
December 1985, Volume ! 1, Number 12
euthyroid Graves’ ophthalmopathy. The duration of preXRT eye signs and symptoms ranged from 2 months to 5 years with a mean of 9 months and a median of 10.5 months. Four patients had visual impairment, but no patient had acute optic neuropathy. Fifteen of 28 patients (54%) had previously been treated with or were receiving steroids at the time of referral. Generally large doses (30-60 mg of Prednisone daily) had been given for many weeks to months. Steroids were tapered off (5 mg per week) once XRT began. Iodineof 15 (60%) had developed significant side effects (agitation, depression, peptic ulcer disease, marked Cushingoid features). Thirteen of 15 patients had failed or had recurrence of symptoms when steroids were tapered off. Seven dditional patients were referred because of absolute or relative contraindications to the use of steroids. Radiotherapy technique A cellulose acetate head and neck treatment shell for immobilization and localization was constructed for all patients. A contour of the shell at the orbital level was used to calculate output factors to achieve a prescribed midline dose of 2000 cGy in 10 fractions over 12 days (Fig. 1). Treatment is delivered on a 4 MeV linear accelerator. The retro-orbital tissues received between 10 1 and 104% of the prescribed dose (Fig. 1). Step I (Figure 2a). The patient is placed supine in the treatment shell. The lateral and midline locating lasers are aligned. The gantry is placed horizontal (0 or I80 degrees). Diaphragm settings establish a 4.0 X 4.0 cm light field. By adjusting the couch height the light field is brought to skim just anterior to the ipsilateral cornea. Step 2. To establish the beam axis (line CD, Fig. 1) parallel to a line tangent to both cornea (line AR, Fig. l), the gantry is rotated exactly 180 degrees and minor adjustments to accommodate unequal amounts of proptosis are made in the couch height and gantry rotation to bring the light field on the second side just anterior to the second cornea. Changes of 2-3 degrees have usually been suffi-
FIG. 1~ Contour in treatment shell. AB is a line tangent to the anterior limits of both cornea. CD, the beam axis, is parallel to and 2.0 cm posterior to line AB. Isodose contours as marked.
XRT for Graves’ ophthalmopathy
I. A.
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FIG. 2. Sequential change in diaphragm settings to establish final treatment portal (c). Shading represents full thickness lead block. See text for details of technique. (a) Step 1, 4.0 X 4.0 cm; (b) Step 3, 8.0 X 4.0 cm; (c) Step 4, 8.0 :< 4.0 with anterior 4 cm blocked with lead.
The gantry is then rotated back 180 degrees to recheck the first side returning the 4.0 X 4.0 light field just anterior to the first cornea. The exact gantry angles are recorded for uniformity of the day to day setup. Step 3 (Fig. 2b). The antero-posterior diaphragm setting is widened to 8.0 cm. Step 4 (Fig. 2~). The anterior 4.0 cm is blocked with 3 inches (7.8 cm) of lead blocking reducing direct transmission to less than 2%. This technique achieves a 4.0 X 4.0 cm treatment portal, the anterior limit of which is aligned along the central axis of the machine and is 2 cm posterior to a line tangent to both cornea. The lead block eliminates divergence anteriorly. The treatment volume encompasses the posterior 0.5 cm of the globe and the entire retrobulbar tissue. Simulator check films are obtained to ensure that the pituitary fossa is excluded posteriorly. All patients are treated bilaterally, because in our experience CT and ultrasound scans demonstrate bilateral involvement, even with minimal signs and symptoms in one eye. We feel the treatment volume as designed encompasses most of the muscular portion of the extraocular muscles since the anterior portion is mainly tendon. Review of CT scans in these patients indicates that it is the posterior 3-s of the muscle that is involved in the inflammatory process. That part of the muscle is included with this technique. Computer simulation estimates a lens dose of less than 5% (100 cGy in 10 fractions in 12 days). Thermoluminescent dosimetric (TLD) readings just anterior to the lateral and medial canthi were performed to confirm this. A mean of three measurements predict a total dose of 98 +- 4.5 cCy. This is less than the estimated cataractogenic dose given as a single exposure.’ This technique varies from Donaldson et ~1.~in (a) the use of a treatment shell for stabilization and localization; (b) the anterior cornea is used as a landmark rather than the lateral bony canthus so that varying degrees of propcient.
tosis can be accommodated, (c) t e anterior beam edge is more sharply defined by the lead blocking rather than by diaphragm settings, and (d) the absence of superior or inferior field blocking. These points should add precision, flexibility and safety especially in minimizing the total lens dose. CT scans Patients underwent orbital CT scans, ultrasonography or both prior to XRT. Bilateral involvement was seen in all patients. Eleven patients were randomly selected to have post-XRT CT scans. These were compared to preXRT scans and correlated with clinical response. Tangential (axial) and coronal scans made it possible to assess muscle changes in the superior, inferior, lateral and medial recti as well as the superior oblique (Fig. 3). The inferior oblique is not well visualized on orbital CT scans. Involvement was scored as 0 = normal, 1 = mild, 2 = moderate and 3 = severe. A CT-muscle index was derived as the sum of the scores of each muscle for each eye separately. The change in the CT muscle index was compared to the change in the ophthalmopathy index in individual patients. Crowding of the optic nerve at the apex of the orbit was scored as 0 = normal fat plane, 1 = diminished fat plane, 2 = encroachment with loss of the fat plane around ~50% ofthe circumference of the optic nerve and 3 = >50% of the circumference of the optic nerve having lost its fat plane. Orbital fat density was difficult to score as density settings and technique varied between scans and was therefore scored simply as normal or increased. RESULTS Clinical’response to radiotherapy Treatment was well tolerated. Five patients had a transient worsening of edema or foreign body sensation, but this cleared by the end of XRT. In this short follow-up (median 17 months) there have been no late XRT effects.
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1985, Volume 11) Number i2
FIG. 3. Left: Pre-XRT; Right: 6 months post-XRT. Left: Axial (a) and coronal (c) scans of patients with a moderate degree of thyroid ophthalmopathy characterized by tearing, lid swelling, widened interpalpebral fissure, chemosis and punctuate staring of the cornea, with limitation of movement and a small esotropian. Total presenting ophthalmopathy index was 4.5. Right: Axial (b) and coronal (d) scans in the same plane as the pretreatment scans. Note diminution in the size of the muscle bellies on both axial and coronal scans. Overall index at the time of second scan was 1.5.
Table 2 outlines the overall response based on the clinical criteria of Donaldson et al.‘j Twenty-six of 28 patients (93%) showed some response. Nineteen of 28 (68%) demonstrated a good to excellent response. There is a trend toward greater improvement in the mean ophthalmopathy indices (Table 3), in association with a better clinical response confirming the index as a useful measure of response. No patients returned entirely to normal. Four patients had initial fair to excellent responses, but then had disease recurrence 3 to 7 months (mean 4.8 months) later. Three have gone on to have orbital decompression, and the fourth is being maintained on corticosteroids. A better response was not seen in patients
with eye signs and symptoms present for less than 12 months compared to those with a longer duration. The soft tissue signs and symptoms responded much more favorably than proptosis or ophthalmoplegia (Table 4). Cornea1 staining resolved in parallel with the reduction in edema and chemosis. The few patients with visual impairment (generally mild) had favorable responses (Table 4). There was no difference in response in the two patients with euthyroid ophthalmopathy compared to those patients who were originally hyper or hypothyroid. There was also no measurable difference in response of either the mean ophthalmopathy index or the likelihood that
XRT for Graves’ ophthalmopathy Table 2. Clinical response Number
Response* Excellent Good Fair Transient No response Worse
Table 3. Change in mean ophthalmopathy
to XRT Percentage
lo/28 9128 3128 4128 2128 O/28
* Response criteria as defined by Donaldson “‘transient”, which refers to disease progression quiring further intervention.
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36 32 11 14 I 0
et al6 except after XRT re-
Response Excellent (lo)* Good (9) Fair (3) Transient (4) No response (2)
index
Pre
Post
Net change
6.5 4.9 5.2 7.1 4.0
3.4 2.5 3.0 4.9 4.5
-3.1 -2.4 -2.2 -2.2 f0.5
* Number of patients in category. Net change in ophthalmopathy index is correlated to response as assessed by clinical criteria.
Teng et al.” reported good recriteria. 1,4,6,1’ sponses in only 35% of their patients, but their population had less severe disease and many had eye symptoms for long durations. The best response in this and other series is on soft tissue signs and symptoms. Transient worsening of symptoms may occur at the start of XRT (5/28: 18% of this series), but this usually resolves by the end of the second week,6 Soft tissue changes respond rapidly (2 to 4 weeks).6,” A better response in those patients with disease symptoms for less than 12 months was not demonstrated in this series in contrast to that reported elsewhere.‘,6,‘6 Nineteen of 28 patients had some degree of measurable proptosis at presentation. The mean reduction was less than 1 mm, confirming the experience of others.‘,6,16 Proptosis responds slowly if at all (3 to 7 months), and patients continue to have more exophthalmos than in normal or hyperthyroid patients without proptosis.i6 Once severe ophthalmoplegia is present only minimal improvement can be expected. None of these patients had acute compressive optic neuropathy. Others have found this to respond rapidly and effectively restoring normal visual acuity in the four such patients reported.‘,6
response
would be completely rea transient flare of symptoms while receiving XRT compared to patients not experiencing such a flare. A total of 14 patients have undergone some surgery post-XRT with four having more than one operation. Three patients required orbital decompression to control symptoms. The rest of the patients had stable disease. Seven muscle recession procedures resulted in 6/7 patients currently with no diplopia w-hile reading or with distance vision. Additionally, seven patients had bilateral blepharoplasties or mullerectomies mainly to improve cosmesis. soft tissue
lieved
signs
and
symptoms
in the five patients
having
Effect on steroid requirements Overall 20/28 patients (7 1%) were referred for failure (8 patients), adverse side effects (5 patients), or relative contraindications to (7 patients) the use of high dose steroids. Seventeen of 20 patients (85%) of this group have no further steroid requirements, In the total group, 4/28 ( 14%) have continued steroid requirements, but the majority, 24/28 (86%) were spared the long-term complications of high dose corticosteroids. Correlation of CT scans with radiotherapy response T, definite changes are seen in all parameters considered (Fig. 3). Nine of 11 patients (82%) had a good correlation between the change in ophthalmopathy index and change in the CT-muscle index. Those patients with an excellent clinical response and greater changes in the ophthalmopathy index had greater changes in the mean CT-muscle score. Patients with no or fair response had smaller CT-muscle index changes and less resolution of apical crowding. The initial degree of involvement as assessed by CT scan was not predictive of the clinical response nor the likelihood of relapse. ISCUSSION
Response Sixty-eight percent of the study population had a good to excellent response, although no patient had eye changes return entirely to normal. This is in agreement with the literature where good to excellent responses have been reported in 35-72% of patients using similar grading and
Radiation technique This technique treats the inflamed retro-orbital tissue, and as it does not rely on bony landmarks, may be used where proptosis is unequal or changes during the course of treatment. Acute XRT side effects are mild and transient. There have been no long-term complications to date in this or other series. 1,6,11The risk of cataractogenesis Table 4. Response
Class 2 3 4 5 6
Present pre-XRT* 28 19 28 13 4
Resolution? 61 21 4 70 50
to XRT vs class
Improved? 32 5 39 15 50
No change? 7 74 57 15 -
* I\Jumber of initial 28 patients with involvement t Percentage of involved pre-XRT Percentage of patients with initial involvement of a given ophthalmopathy sign showing improvement post-XRT. Resolution. = complete disappearance or return to normal. Improved = some improvement but less than resolution
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and hypopituitarism are negligible with the dose delivered to those structures by this technique. Although there are reports of second malignancy arising after XRT for benign diseases,3,9 the risk in this setting is felt to be small. The alternative to XRT has generally been the use of corticosteroids. No randomized trials comparing XRT alone vs steroids alone have been reported. Bartalena et al. ’recently reported a trial comparing orbital cobalt XRT with steroids vs steroids alone (70-80 mg Methylprednisolone X 3 weeks then slowly tapering over 5-6 months). Combined treatment gave significantly better results than steroids alone. However, “most cases” developed Cushingoid features.] In our experience, similar steroid doses have been required in order to control disease manifestations, resulting in significant and limiting side effects. Five patients (18%) were initially referred because of limiting adverse effects and seven (25%) because of relative contraindications to the use of high dose steroids. Additionally, in this population and others6,“j failure on or relapse after steroid use was not predictive of a lack of response to XRT. Twenty-four of 28 patients (86%) in this series have had no further steroid requirements postXRT. We feel this reduction in steroid use is a significant benefit. There may be a subgroup of patients who will respond to either XRT or steroids. To minimize toxicity we recommend the early use of XRT in those patients not easily controlled by a short course of modest dose steroids, and in elderly patients. Orbital CT scans7 and ultrasonography” have been useful diagnostically. Extraocular muscle and orbital fat
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changes parallel clinical response post-XRT (Fig. 3). The severity of initial involvement as assessed by CT scan, however, is not predictive of either the degree of response nor the likelihood of relapse. Several questions remain about the use of XRT in Graves’ ophthalmopathy, not the least of which is, why does it work? Local immunosuppression is attractive theoretically and was the initial impetus for the trial of this modality. If an aberrant, systemic immune response is the basis of the disease process, it is surprising that symptomatic recurrence is not more common. Possibly the XRT interferes with a target other than inflammatory cells, such as the fibroblast or muscle membrane components, to prevent the development of infiltrative changes.6 In summary, with the described technique, a good to excellent response can be expected in approximately 70% of patients with negligible acute or long-term complications. XRT is indicated for: 1. Rapidly progressive severe ophthalmopathy. 2. Troublesome soft tissue signs and symptoms. 3. Patients in whom steroids are contraindicated. 4. Patients not controlled by or developing side effects on modest doses of steroids.
The effect of XRT as a primary modality in very early disease is not known. Potentially XRT may permanently arrest disease progression and prevent the disabling and disfiguring problems associated with proptosis and ophthalmoplegia. The role of XRT in this early group is currently being assessed at our institution.
REFERENCES 1. Bartalena, L., Marcocci, C., Chiovata, L., Laddaga, M., Lepri, G., Andreani, D., Cavallacci, G., Baschieri, L., Pinchera, A.: Orbital cobalt irradiation combined with systemic corticosteroids for Graves’ ophthalmopathy: Comparison with systemic corticosteroids alone. J. Clin. Endocrinol. Metab. 56(6): 1139-l 144, 1983. 2. Burrow, G.N., Mitchell, MS., Howard, R.O.: Immunosuppressive therapy for the eye changes of Graves’ disease. J. C/in. Endocrinol. 31: 307-311, 1970. 3. Court Brown, W.M., Doll, R.: Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. Br. Med. J. 2: 1327-1332, 1965. E.E., Lobes, L., Sudarsanam, A.: Radiation 4. Covington, therapy for exophthalmos: Report of seven cases. Radiology 122: 797-799, 1977. 5. Dandona, P., Marshall, N.J., Bidey, S.P., Nathan, A., Havard, C.W.H.: Successful treatment of exophthalmas and Br. Med. J. 1: pretibial myxoedema with plasmapheresis. 374-376, 1979. 6. Donaldson, S.S., Bagshaw, M.A., Kriss, V.P.: Supervoltage J. Clin. orbital radiotherapy for Graves’ ophthalmopathy. Endocrinol. Metab. 37(2): 276-285, 1973. 7. Feldon, SE., Weiner, J.M.: Clinical significance of extraocular muscle volumes in Graves’ ophthalmopathy: A quantitative computed tomography study. Arch. Ophthalmol. lOO(8): 1266-1269, 1982. 8. Merriam, Jr. G.R., Focht, E.F.: A clinical study of radiation cataracts and the relationship to dose. Am. J. Roentgenol. 77: 759-785, 1957.
9. Saenger, EL., Silverman, F.N., Sperling, T.D., Turner, M.E.: Neoplasia following therapeutic irradiation for benign conditions in childhood. Radiology 74(6): 889-904, 1960. A clin10. Sergott, R.C., Glaser, J.S.: Graves’ ophthalmopathy. ical and immunologic review. Surv. Ophthalmol. 26( 1): l21, 1981. 11. Teng, C.S., Crombie, A.L., Hall, R., Ross, W.M.: An evaluation of supervoltage orbital irradiation for Graves’ ophthalmopathy. Chin. Endocrinol. (Oxf.) 13(6): 545-55 1, 1980. 12. Wall, J.R., Strakosch, C.R., Fang, S.L., Ingbar, S.H., Braverman, L.E.: Thyroid binding antibodies and other immunological abnormalities in patients with Graves’ ophthalmopathy: Effect of treatment with Cyclophosphamide. Clin. Endocrinol. (Osf.) lO( 1): 79-9 1, 1979. 13. Weetman, A.P., Ludgate, M., Mills, P.V., McGregor, A.M., Beck, L., Lazarus, J.H., Hall, R.: Cyclosporin improves Graves’ ophthalmopathy. Lancet 2: 486-489, 1983. 14. Werner, SC.: Classification of the eye changes of Graves’ disease. J. Clin. Endocrinol. 29: 982-984, 1969. 15. Yamamoto, K., Itoh, K., Yoshida, S., Saito, K.; Sakamoto, Y., Matsuda, A., Saito, T., Kuzuya, T.: A quantitative analysis of orbital soft tissues in Graves’ disease based on Bmode ultrasonography. Endocrinol. Jpn. 26(2): 255-26 1, 1979. 16. Yamamoto, K., Saito, K., Takai, T., Yoshida, S.: Treatment of Graves’ ophthalmopathy by steroid therapy, orbital radiation therapy, plasmapheresis and thyroxine replacement. Endocrinol. Jpn. 29(4): 495-50 1, 1982.